There are a number of vision-threatening disorders or diseases of the eye of a mammal including, but not limited to diseases of the retina, retinal pigment epithelium (RPE) and choroid. Such vision threatening diseases include ocular neovascularization, ocular inflammation and retinal degenerations. Examples of these disease states include diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, age-related macular degeneration, retinal neovascularization, subretinal neovascularization; rubeosis iritis inflammatory diseases, chronic posterior and pan uveitis, neoplasms, retinoblastoma, pseudoglioma, neovascular glaucoma; neovascularization resulting following a combined vitrectomy-2 and lensectomy, vascular diseases, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, neovascularization of the optic nerve, diabetic macular edema, cystoid macular edema, macular edema, retinitis pigmentosa, retinal vein occlusion, proliferative vitreoretinopathy, angioid streak, and retinal artery occlusion, and neovascularization due to penetration of the eye or ocular injury.
Age-related macular degeneration (AMD) is the leading cause of irreversible severe central vision loss in Caucasians fifty years old and older in the United States. According to the 1990 U.S. census, approximately 750,000 people over 65 years of age were estimated as severe visual impairment in one or both eyes from AMD. Also, the number of cases of AMD has been predicted to increase from 2.7 million in 1970 to 7.5 million by the year 2030.
Roughly 80 percent of the AMD cases involve non-neovascular conditions, for which there are no effective treatments. For the remaining cases involving neovascularization, currently available treatments are sub-optimal. Perhaps the best known therapy is photodynamic therapy (PDT), however, while this therapy has received significant attention in both the ophthalmic and financial investment communities, it is useful in only about 20 percent of neovascular AMD cases. In addition, this particular therapy is not a simple or inexpensive treatment. The procedure generally needs to be repeated every three months for at least two years, with approximate total cost of $12,250.
A number of angiostatic agents are currently under investigation for the treatment of AMD. Thalidomide, for example, is known to be a powerful angiostatic agent. Its systemic side effects, however, include peripheral neuropathy, central nervous system depression, and embryotoxicity. In addition, these systemic side effects have limited the dosage administered to patients for the treatment of subretinal neovascularization. Systemic inhibition of angiogenesis in older patients can also interfere with the development of collateral circulation, which has a role in the prevention of central nervous system as well as cardiac ischemic events.
A number of techniques or methodologies have been developed to deliver drugs to the various tissues or structure that make up the mammalian eye, as described hereinafter, to treat a wide range of disorders or diseases of the eye. However, delivery of drugs, proteins and the like to the eye(s) of mammals in order to achieve the desired therapeutic or medical effect, especially to the retina and/or the choroid, has proved to be challenging, owing in large part to the geometry, delicacy and/or behavior of the eye and its components. A brief description of various conventional methods or techniques for delivering drugs to the tissues of the eye and the shortcomings thereof is summarized.
Oral ingestion of a drug or injection of a drug at a site other than the eye can provide a drug systemically, however such a systemic administration does not provide effective levels of the drug specifically to the eye. In many ophthalmic disorders involving the retina, posterior tract, and optic nerve, adequate levels of the drug cannot be achieved or maintained by oral or parenteral routes of administration. Thus, further and repeated administration of the drug would be necessary to achieve the desired or adequate levels of concentration of the drug. Such further and repeated administrations of such drugs may produce undesired systemic toxicity.
Ophthalmic conditions have also been treated using drugs applied directly to the eye in either liquid or ointment form. This route of administration (i.e., topical administration) is only effective in treating problems involving the superficial surface of the eye and diseases that involve the cornea and anterior segment of the eye, such as conjunctivitis. Topical administration of drugs is not effective in achieving adequate concentrations of a drug(s) in the sclera, vitreous, or posterior segment of the eye. In addition, topical eye drops may drain from the eye through the nasolacrimal duct and into the systemic circulation, further diluting the medication and risking unwanted systemic side effects. Furthermore, delivery of drugs in the form of topical eye drops is also of little utility because the drug cannot cross the cornea and be made available to the vitreous, retina, or other subretinal structures such as the retinal pigment epithelium (“RPE”) or choroidal vasculature. Some drugs are highly unstable and therefore not easily formulated for topical delivery. Moreover, data also indicate that it is not unusual for up to 85% of topically applied agents to he removed by the eye's blink mechanism/reflex.
Direct delivery of drugs to the eye by a topical insert has also been attempted, however, this method is not desirable. Such topical inserts require patient self-administration and thus education on their insertion into and removal from the eye. Consequently, this technique demands a certain degree of manual dexterity that can be problematic for geriatric patients who are particularly susceptible to certain eye disorders that appear age related (e.g., age related macular degeneration). In many instances such topical inserts may cause eye irritation and such inserts are prone to inadvertent loss due to eyelid laxity. In addition, these devices provide a source of drug only to the cornea and anterior chamber, and thus do not provide any pharmacologic advantage over topical eye drops or ointments. Such devices therefore have limited, if any at all, utility for providing an effective source of drugs to the vitreous or tissues located in the posterior segment of the eye.
Consequently, most methods for treating eye disorders or diseases in the posterior segment, or the back-of-the-eye, involve intravitreal delivery of the drug. One such technique for intravitreal delivery is accomplished by intraocular injection of the drug or microspheres containing the drug directly into the vitreous or by locating a device or capsule containing the drug in the vitreous, such as that described in U.S. Pat. No. 5,770,589. Intravitreal injection of a drug is an effective means of delivering the drug to the posterior segment of the eye in high concentrations, but it is not without its shortcomings. It is well known that drugs that are initially located within the vitreous are removed from the vitreous over time via the anterior segment of the eye. If the ocular condition is anything other than acute, this technique necessarily requires follow-up injections in order to maintain an adequate therapeutic concentration within the vitreous. This, in turn, presents problems because each additional intraocular injection carries with it a realistic risk of infection, hemorrhage and/or retinal detachment.
It also is well known that many therapeutic drugs cannot easily diffuse across the retina. The dose being administered and maintained in the vitreous has to take into account the amount that can diffuse across the retinal boundary as well as how long the drug is retained in effective amounts within the vitreous. It has been observed from animal studies that 72 hours after injection of triamcinolone, less than 1% of the triamcinolone present in the vitreous is associated with other tissues including the retina, pigment epithelium, and sclera.
In addition to concerns relating to the relative effectiveness of drug delivery across the barrier, complications or side effects have been observed when using a direct injection into vitreous technique with some therapeutics. For example, corticosteroid compounds, such as triamcinolone, can effectively treat some forms of neovascularization such as corneal neovasularization. When these compounds are used to treat neovascularization of the posterior segment by direct injection, undesirable side effects can be caused in many patients. The adverse affects or undesirable side effects included elevations in intraocular pressure and the formation of, or acceleration of, the development of cataracts. Elevations in intraocular pressure are of particular concern in patients who are already suffering from elevated intraocular pressure, such as glaucoma patients. Moreover, there is a risk in using corticosteroids in patients with normal intraocular pressure because of elevations in pressure that can result in damage to ocular tissue. Since therapy with corticosteroids is frequently long term, i.e., several days or more, a potential exists for significant damage to ocular tissue as a result of prolonged elevations in intraocular pressure attributable to that therapy.
Consequently, investigations in the area of intravitreal delivery also have focused on developing a sustained release implant, capsule or other such device or mechanism that is in communication with the vitreous and which is configured so as to provide a release over time into the vitreous of the contained drug. Examples of such controlled release devices are described in U.S. Pat. Nos. 6,217,895; 5,773,019; 5,378,475; and U.S. Patent Application Publication No. 2002/0061327.
A common feature of the techniques/instruments described in these references, is that a surgical incision is required at the outset of a procedure so that the implant, capsule or other such device can be inserted through the eye and located in the vitreous. These methods and techniques also necessarily involve the use of sutures following completion of the procedure to seal or close the incision in order to prevent loss of vitreous material. As is known to those skilled in the art, maintaining the volume of the posterior segment or vitreous is necessary to maintaining the shape and optical arrangement of the eye. Such a course of treatment also increases the duration and cost as well as the realistic risks of corneal ulceration, cataract formation, intraocular infection, and/or vitreous loss that accompany these procedures.
U.S. Pat. Nos. 5,273,530 and 5,409,457 describe an instrument and methodology to transplant donor cells, more specifically donor retina cells, in the subretinal space. The instrument is also described as useful for injecting or removing material from the vitreous. According to the described methodology, the instrument is shaped and dimensioned so it can be inserted into an eye orbit along an insertion path that extends along the periphery of the eye in order to place the tip adjacent to the retina or sub-retinal region. The tip is then moved generally in the medial direction so that the tip pierces the exterior of the eye and resides in the sub-retinal region or in the vitreous, depending upon how much the tip is moved. In order to prevent over-insertion of the tip, a collar is provided about the tip in order to limit the distance the tip can be inserted into the eye.
U.S. Patent Application Publication 2002/0055724 describes an instrument for sub-retinal transplantation of retinal cells, epithelium and choroid within their normal planar configuration as a graft into the sub-retinal region of an eye. The described instrument is inserted into an opening in the eye using either a transcorneal surgical approach or a trans-choroidal and scleral surgical approach. According to this technique, the instrument is advanced under the retina to detach the retina so that the graft can be inserted. As noted in U.S. Pat. No. 5,273,530, the penetration of the anterior part or segment of the eye, using the transcorneal or the transscleral route creates the risk of corneal ulceration, cataract formation and other anterior penetration problems. Also using either approach, a surgical incision is created at the outset of a procedure so that the instrument can be inserted and sutures are used following completion of the procedure to seal or close the incision inn order to prevent loss of vitreous material (i.e., aqueous humor).
The delivery of drugs to the eye presents significant challenges. The ocular absorption of systemically administered pharmacologic agents is limited by the blood ocular barrier, namely the tight junctions of the retinal pigment epithelium and vascular endothelial cells. High systemic doses of therapeutic drugs can penetrate this blood ocular barrier in relatively small amounts, but may expose the patient to the risk of systemic toxicity. Topical delivery of drugs often results in limited ocular absorption due to the complex hydrophobic/hydrophilic properties of the cornea and sclera. Additionally, topical agents are mechanically removed by the blink mechanism such that only approximately 15% of a single drop is absorbed. Diffusion of topically administered drugs to the posterior chamber occurs, but often at sub-therapeutic levels. Intravitreal injection of drugs is an effective means of delivering a drug to the posterior segment in high concentrations. However, repeated intraocular injections carry the risk of infection, hemorrhage and retinal detachment. Patients also find this procedure somewhat difficult to endure, resulting in high rates of noncompliance.
Local sustained delivery of therapeutics to the posterior chamber is particularly critical in managing several chronic diseases of the eye. In attempts to address this need, several drug delivery devices have been developed for intraocular insertion into the vitreous region of the eye.
U.S. Pat. No. 4,300,557, for example, describes an intraocular implant in the form of a silicone capsule, which can be filled with a drug to be delivered. The implant is inserted through an incision into the vitreous region of the eye. After insertion of the implant, the incision is closed and the capsule remains in place for a period of time. Attached to the implant is a tube that passes through the surface of the eye. The tube may be used for subsequent injection of a drug while the implant is in the eye. The implant may be removed by making a second surgical incision into the eye and retrieving the implant. While in the vitreous, the device is not anchored and may move about freely. Because the overall shape of the capsule is linear, the amount of drug held by the device and delivered over the surface area of the device is limited. If the width of the capsule is increased, excessive sized incisions will be required for insertion of the device. If the length of the capsule is increased to greater than 1 cm, the implant will pass into the central visual field of the eye, causing blind spots in the patient's eye as well as increased risk of damage to the retinal tissue and lens capsule.
U.S. Pat. No. 5,378,475 describes a device which has been developed for insertion in the vitreous region of the eye, and is described in T. J. Smith et al., Sustained Release Ganciclovir, Arch. Ophthalmol, 110, 255-258 (1992) and G. E. Sanborn, et al., Sustained-Release Ganciclovir Therapy for Treatment of Cytomegalovirus Retinitis; Use of an Intravitreal Device, Arch. Ophthalmol, 110, 188-195 (1992). This device consists of an inner core of pharmacologic agent surrounded by two coatings with different permeabilities. Drug diffuses through a small opening in one of these coatings achieving near zero-order release kinetics. It is implanted in the region of the pars plana through a 3.55.0 mm scleral incision. The implant must be removed and replaced every 6 months in the operating room as the drug becomes depleted. There is an approximately 25% complication rate from these procedures. The device is a membrane diffusion drug delivery system that relies on EVA/PVA polymers to mediate release rate. However, many agents cannot be effectively delivered from such a system because their permeation rate through the rate controlling material of the system is too small to produce a useful effect. Other agents cannot be satisfactorily delivered by diffusional devices because of a particular chemical characteristic of the agent. This includes salts, because of their ionic character, and unstable polar compounds that cannot be formulated into a composition suitable for storage and delivery from such systems.
U.S. Pat. No. 5,098,443 describes certain specific implants that are inserted through incisions made in the eye wall or sutured around the globe of the eye. These rings may be formed from biodegradable polymers containing microparticles of drug. Alternatively, the implant may be in the form of a hollow flexible polymeric cocoon with the drug disposed therewithin for slow release by osmosis. No anchoring device is described.
U.S. Pat. No. 5,466,233 describes a certain tack for intraocular drug delivery. This device has an end that is positioned in the vitreous cavity while the head remains external to the eye and abuts the scleral surface. The tack contains a fixation portion to attempt to retain attachment within the eye. Because the overall shape of the capsule is linear, the amount of drug that may be held by the device and the surface area through which the drug may be delivered is limited. If the width of the capsule is increased, excessive sized incisions will be required for insertion of the device. If the length of the capsule is increased to greater than 1 cm, the implant will pass into the central visual field of the eye, thereby causing blind spots in the patient's eyes well as increase risk of damage to the retinal tissue and lens capsule.
In view of the above, it would be desirable to provide additional methods and devices for treating the eye, particularly treating retinal and/or choroidal conditions.